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1.  The joint associations between F5 gene polymorphisms and maternal smoking during pregnancy on preterm delivery 
Human genetics  2008;124(6):659-668.
Factor V (F5) genetic variants and maternal smoking during pregnancy individually has been associated with increased risk of preterm delivery (PTD). We hypothesize that F5 gene and maternal smoking may synergistically increase the risk of PTD. Three single nucleotide polymorphisms (SNPs) in F5 gene (rs6019, rs2213869 and rs6022) were genotyped in 542 mothers with PTD and 1,141 mothers with term deliveries at the Boston Medical Center. The individual and interactive effects of F5 SNPs and maternal smoking on PTD and gestational age were examined, respectively. The results suggested that maternal smoking, three F5 SNPs and F5 haplotype were individually associated with PTD and gestational age. More importantly, we found significant interactions between the two F5 SNPs (rs6019 and rs6022) and maternal smoking on PTD and gestational age. Compared with non-smoking mothers carrying rs6019 GG genotype, persistently smoking mothers carrying genotypes GC or CC were associated with significantly increased risk of PTD (OR(95%CI): 2.1(1.2–3.6) for GC; 5.7(2.1–15.0) for CC; p-interaction=0.02). A significant interaction was also observed for gestational age. Similar pattern of interactions was found between rs6022 and maternal smoking on PTD. In summary, our data indicated that F5 gene variants and maternal smoking may synergistically increase the risk of PTD.
doi:10.1007/s00439-008-0589-2
PMCID: PMC4986615  PMID: 19020903
2.  Characterization of selective and potent PI3Kδ inhibitor (PI3KD-IN-015) for B-Cell malignances 
Oncotarget  2016;7(22):32641-32651.
PI3Kδ is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3Kd inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KD-IN-015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate anti-proliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies.
doi:10.18632/oncotarget.8702
PMCID: PMC5078040  PMID: 27081697
PI3Kδ; leukemia; B-cell malignances; PI3K; kinase inhibitors
3.  Dual inhibition of AKT/FLT3-ITD by A674563 overcomes FLT3 ligand-induced drug resistance in FLT3-ITD positive AML 
Oncotarget  2016;7(20):29131-29142.
The FLT3-ITD mutation is one of the most prevalent oncogenic mutations in AML. Several FLT3 kinase inhibitors have shown impressive activity in clinical evaluation, however clinical responses are usually transient and clinical effects are rapidly lost due to drug resistance. One of the resistance mechanisms in the AML refractory patients involves FLT3-ligand induced reactivation of AKT and/or ERK signaling via FLT3 wt kinase. Via a screen of numerous AKT kinase inhibitors, we identified the well-established orally available AKT inhibitor, A674563, as a dual suppressor of AKT and FLT3-ITD. A674563 suppressed FLT3-ITD positive AML both in vitro and in vivo. More importantly, compared to other FLT3 inhibitors, A674563 is able to overcome FLT3 ligand-induced drug resistance through simultaneous inhibition of FLT3-ITD- and AKT-mediated signaling. Our findings suggest that A674563 might be a potential drug candidate for overcoming FLT3 ligand-mediated drug resistance in FLT3-ITD positive AML.
doi:10.18632/oncotarget.8675
PMCID: PMC5045383  PMID: 27074558
acute myeloid leukemia; FLT3-ITD; AKT; A6745763; FLT3-ligand
4.  Relationship of anthropometric measurements to thyroid nodules in a Chinese population 
BMJ Open  2015;5(12):e008452.
Objective
Previous studies have found that overweight and obesity are related to numerous diseases, including thyroid cancer and thyroid volume. This study evaluates the relationship between body size and the presence of thyroid nodules in a Chinese population.
Methods
A total of 6793 adults and 2410 children who underwent thyroid ultrasonography were recruited in this cross-sectional study in Hangzhou, Zhejiang Province, China, from March to October, 2010. Sociodemographic characteristics and potential risk factors of thyroid nodules were collected by questionnaire. Height and weight were measured using standard protocols. Associations of height, weight, body mass index (BMI) and body surface area (BSA) with the presence of thyroid nodules were evaluated using multiple logistic regression models.
Results
After adjustment for potential risk factors, an increased risk of thyroid nodule incidence was associated with height (OR 1.15, 95% CI 1.02 to 1.30), weight (OR 1.40, 95% CI 1.24 to 1.58), BMI (OR 1.26, 95% CI 1.11 to 1.42) and BSA (OR 1.43, 95% CI 1.27 to 1.62) in all adults, but most obviously in women. In children, similar associations were observed between risk of thyroid nodule incidence and weight, BMI and BSA, but not height. BSA was the measurement most significantly associated with thyroid nodules in both adults and children.
Conclusions
This study identified that the presence of thyroid nodules was positively associated with weight, height, BMI and BSA in both women and girls. It suggests that tall, obese individuals have increased susceptibility to thyroid nodules.
Trial registration number:
NCT01838629.
doi:10.1136/bmjopen-2015-008452
PMCID: PMC4691709  PMID: 26692553
EPIDEMIOLOGY; STATISTICS & RESEARCH METHODS
5.  Associations between gene polymorphisms in fatty acid metabolism pathway and preterm delivery in a US urban black population 
Human genetics  2011;131(3):341-351.
There is increasing evidence suggesting that higher intakes of fish or n-3 polyunsaturated fatty acids supplements may decrease the risk of preterm delivery (PTD). We hypothesized that genetic variants of the enzymes critical to fatty acids biosynthesis and metabolism may be associated with PTD. We genotyped 231 potentially functional single nucleotide polymorphisms (SNPs) and tagSNPs in 9 genes (FADS1, FADS2, PTGS1, PTGS2, ALOX5, ALOX5AP, PTGES, PTGES2, and PTGES3) among 1,110 black mothers, including 542 mothers who delivered preterm (<37 weeks gestation) and 568 mothers who delivered full-term babies (≥37 weeks gestation) at Boston Medical Center. After excluding SNPs that are in complete linkage disequilibrium or have lower minor allele frequency (<1%) or call rate (<90%), we examined the association of 206 SNPs with PTD using multiple logistic regression models. We also imputed 190 HapMap SNPs via program MACH and examined their associations with PTD. Finally, we explored gene-level and pathway-level associations with PTD using the adaptive rank truncated product (ARTP) methods. A total of 21 SNPs were associated with PTD (p value ranging from 0.003 to 0.05), including 3 imputed SNPs. Gene-level ARTP statistics indicated that the gene PTGES2 was significantly associated with PTD with a gene-based p value equal to 0.01. No pathway-based association was found. In this large and comprehensive candidate gene study, we found a modest association of genes in fatty acid metabolism pathway with PTD. Further investigation of these gene polymorphisms jointly with fatty acid measures and other genetic factors would help better understand the pathogenesis of PTD.
doi:10.1007/s00439-011-1079-5
PMCID: PMC4547931  PMID: 21847588
6.  Maternal Preconception Body Mass Index and Offspring Cord Blood DNA Methylation: Exploration of Early Life Origins of Disease 
Maternal obesity is associated with a variety of common diseases in the offspring. One possible underlying mechanism could be maternal obesity induced alterations in DNA methylation. However, this hypothesis is yet to be tested. We performed epigenomic mapping of cord blood among 308 Black mother-infant pairs delivered at term at the Boston Medical Center using the Illumina HumanMethylation27 BeadChip. Linear regression and pathway analyses were conducted to evaluate the associations between DNA methylation levels and prepregnancy maternal BMI (<25, 25–30, ≥30 kg/m2). The methylation levels of 20 CpG sites were associated with maternal BMI at a significance level of P-value <10−4 in the overall sample, and boys and girls, separately. One CpG site remained statistically significant after correction for multiple comparisons (FDR corrected P-value = 0.04) and was annotated to a potential cancer gene, ZCCHC10. Some of the other CpG site annotated genes appear to be critical to the development of cancers and cardiovascular diseases (i.e., WNT16, C18orf8, ANGPTL2, SAPCD2, ADCY3, PRR16, ERBB2, DOK2, PLAC1). Significant findings from pathway analysis, such as infectious and inflammatory and lipid metabolism pathways, lends support for the potential impact of maternal BMI on the above stated disorders. This study demonstrates that prepregnancy maternal BMI might lead to alterations in offspring DNA methylation in genes relevant to the development of a range of complex chronic diseases, providing evidence of trans-generational influence on disease susceptibility via epigenetic mechanism.
doi:10.1002/em.21827
PMCID: PMC4547934  PMID: 24243566
maternal BMI; cord blood; DNA methylation; early life origins of disease
7.  Elevated Serum Levels of NSE and S-100β Correlate with Increased Risk of Acute Cerebral Infarction in Asian Populations 
Background
We investigated the clinical value of serum levels of neuron-specific enolase (NSE) and human soluble protein-100β (S-100β) in acute cerebral infarction (ACI) patients.
Material/Methods
A literature search of electronic databases identified relevant case-control studies that examined the correlations between NSE and S-100β serum levels, and ACI. The retrieved studies were screened based on our strict inclusion and exclusion criteria, and high-quality studies were subsequently selected for meta-analysis. STATA software (Version 12.0, Stata Corporation, College Station, TX, USA) was utilized for statistical analysis.
Results
A total of 13 case-control studies, containing 911 ACI patients and 686 healthy controls, were enrolled in this meta-analysis. The results of the meta-analysis showed that serum levels of NSE and S-100β in ACI patients were significantly higher than the control group. Subgroup analysis based on ethnicity revealed that the serum levels of NSE and S-100β in ACI patients were significantly higher than the control group in Asian population. In Caucasian population, the serum levels of NSE in case group was significantly higher than the control group, but no significant differences in serum levels of S-100β were observed between ACI patients and the control group.
Conclusions
Based on our results, we conclude that serum levels of NSE and S-100β strongly correlate with ACI in Asian population, and may be important clinical markers for diagnosis and treatment of ACI.
doi:10.12659/MSM.893615
PMCID: PMC4492484  PMID: 26124190
Brain Abscess; Diagnosis; Infarction, Anterior Cerebral Artery; Meta-Analysis; Phosphopyruvate Hydratase; Technetium Tc 99m Aggregated Albumin
8.  The Combined Association of Psychosocial Stress and Chronic Hypertension with Preeclampsia 
American journal of obstetrics and gynecology  2013;209(5):10.1016/j.ajog.2013.07.003.
OBJECTIVE
This study aims to evaluate perceived lifetime stress (LS), perceived stress during pregnancy (PS), chronic hypertension (CH) and their joint association with preeclampsia risk.
STUDY DESIGN
This study includes 4,314 women who delivered a singleton live birth at the Boston Medical Center from October 1998 through February 2008. CH is defined as hypertension diagnosed before pregnancy. Information regarding LS and SP was collected by questionnaire. Preeclampsia was diagnosed by clinical criteria.
RESULTS
LS, SP and CH were each associated with an increased risk of preeclampsia (OR(95%CI)=2.1(1.6–2.8) for LS; 1.7(1.3–2.1) for SP; 11.1(8.1–15.4) for CH). Compared with normotensive pregnancy with low LS, both normotensive pregnancy with high LS (2.1(1.5–2.9)) and pregnancy with CH and low LS (10.6(7.5–15.1)) showed an increased risk of preeclampsia, while pregnancy with high LS and CH yielded the highest risk of preeclampsia (21.3(10.3–44.3)). The joint association of SP and CH on preeclampsia was very similar to that of the joint association of LS and CH.
CONCLUSIONS
This finding indicates that high psychosocial stress and CH can act in combination to increase the risk of preeclampsia up to 20-fold. This finding underscores the importance of efforts to prevent, screen and manage CH, along with reducing psychosocial stress, particularly among women with CH.
doi:10.1016/j.ajog.2013.07.003
PMCID: PMC3825759  PMID: 23850528
Psychosocial stress; chronic hypertension; combined effect; preeclampsia
9.  Occupational Electromagnetic Field Exposures Associated with Sleep Quality: A Cross-Sectional Study 
PLoS ONE  2014;9(10):e110825.
Background
Exposure to electromagnetic field (EMF) emitted by mobile phone and other machineries concerns half the world’s population and raises the problem of their impact on human health. The present study aims to explore the effects of electromagnetic field exposures on sleep quality and sleep duration among workers from electric power plant.
Methods
A cross-sectional study was conducted in an electric power plant of Zhejiang Province, China. A total of 854 participants were included in the final analysis. The detailed information of participants was obtained by trained investigators using a structured questionnaire, which including socio-demographic characteristics, lifestyle variables, sleep variables and electromagnetic exposures. Physical examination and venous blood collection were also carried out for every study subject.
Results
After grouping daily occupational electromagnetic exposure into three categories, subjects with long daily exposure time had a significantly higher risk of poor sleep quality in comparison to those with short daily exposure time. The adjusted odds ratios were 1.68 (95%CI: 1.18, 2.39) and 1.57 (95%CI: 1.10, 2.24) across tertiles. Additionally, among the subjects with long-term occupational exposure, the longer daily occupational exposure time apparently increased the risk of poor sleep quality (OR (95%CI): 2.12 (1.23∼3.66) in the second tertile; 1.83 (1.07∼3.15) in the third tertile). There was no significant association of long-term occupational exposure duration, monthly electric fee or years of mobile-phone use with sleep quality or sleep duration.
Conclusions
The findings showed that daily occupational EMF exposure was positively associated with poor sleep quality. It implies EMF exposure may damage human sleep quality rather than sleep duration.
doi:10.1371/journal.pone.0110825
PMCID: PMC4207748  PMID: 25340654
10.  The Association of Thyroid Nodule with Non-Iodized Salt among Chinese Children 
PLoS ONE  2014;9(7):e102726.
Objective
The controversy that iodized salt may increase the risk of thyroid disorders has been aroused in China during the past decade. Most of studies focused on adult rather than children. We aimed to explore whether iodized salt was associated with an increased risk of thyroid nodule in Chinese children.
Methods
The cross-sectional study was conducted in Hangzhou, China, in 2010. Iodized salt intake, urine iodine concentration (UIC) and thyroid nodule (by ultrasonography) were measured in 3026 children. The associations of iodized salt with thyroid nodule were evaluated using multiple logistic regression models.
Results
The prevalence of thyroid nodule was 10.59% among Chinese children. Girls (11.89%) had higher prevalence of thyroid nodule than boys (9.26%). No significant association was observed between type of salt and thyroid nodule in pooled samples, boys and girls, respectively. Similar associations were observed between UIC and thyroid nodule. There was no significant association between milk consumption and thyroid nodule as well.
Conclusion
The present study indicated that non-iodized salt may not increase the risk of thyroid nodules among Chinese children. Similar associations were observed between milk consumption, UIC and thyroid nodules.
doi:10.1371/journal.pone.0102726
PMCID: PMC4113344  PMID: 25068269
11.  Genetic and Environmental Contributions to Phenotypic Components of Metabolic Syndrome: A Population-based Twin Study 
Obesity (Silver Spring, Md.)  2009;17(8):1581-1587.
The increasing prevalence of metabolic syndrome (MS) poses a serious public health problem worldwide. Effective prevention and intervention require improved understanding of the factors that contribute to MS. We analyzed data on a large twin cohort to estimate genetic and environmental contributions to MS and to major MS components and their inter-correlations: waist circumference, systolic and diastolic blood pressure, fasting plasma glucose, triglycerides, and high density lipoprotein cholesterol. We applied structural equation modeling to determine genetic and environmental structure of MS and its major components, using 1,617 adult female twin pairs recruited from rural China. The heritability estimate for MS was 0.42 (95% CI: 0.00–0.83) in this sample with low MS prevalence (4.4%). For MS components, heritability estimates were statistically significant and ranged from 0.13 to 0.64 highest for WC, followed by TG, SBP, DBP, HDL-C, and FPG. HDL-C was mainly influenced by common environmental factors (0.62, 95%CI: 0.58–0.62), while the other five MS components were largely influenced by unique environmental factors (0.32–0.44). Bivariate Cholesky decomposition analysis indicated that the clinical clustering of MS components may be explained by shared genetic and/or environmental factors. Our study underscores the importance of examining MS components as inter-correlated traits, and to carefully consider environmental and genetic factors in studying MS etiology.
doi:10.1038/oby.2009.125
PMCID: PMC3766632  PMID: 19407809
metabolic syndrome; twin study; heritability; Chinese
12.  Association of Adiposity Trajectories With Insulin Sensitivity and Glycemic Deterioration 
Diabetes Care  2012;35(7):1506-1512.
OBJECTIVE
To evaluate associations between adiposity trajectories over time and insulin sensitivity and glucose deterioration in a Chinese twin cohort.
RESEARCH DESIGN AND METHODS
This study focused on 341 males and 292 females aged 20–50 years at baseline who had physical clinical examinations and oral glucose tolerance test at two time points with an average of 6 years apart. BMI, waist circumference, percent body fat (PBF), and percent trunk fat (PTF) trajectories were classified into five track groups based on age- and sex-specific tertiles at each visit. We calculated the odds of the insulin sensitivity index(0,120) [ISI(0,120)] or glycemic deterioration at follow-up among five defined trajectories (tertilebaseline → tertilefollow-up) using generalized estimate equation models. Additionally, we applied structural equation models to examine genetic and environmental influences on adiposity, adiposity change over time (ACO), ISI(0,120), and the interrelationships among them.
RESULTS
Participants with stable adiposity (BMI, waist circumference, PBF, and PTF) in the highest tertile or shifting to the highest tertile tended to have the lowest ISI(0,120) at follow-up or experience glycemic deterioration. Genetic factors exerted the major influence on adiposity, but environmental factors unique to each twin contributed more strongly to ISI and ACO. Correlations between adiposity/ACO and insulin sensitivity were mainly due to environmental influences.
CONCLUSIONS
When adiposity stays or becomes high, insulin sensitivity falls and risk of glycemic deterioration rises. Additionally, we found that genetic factors exerted the major influence on adiposity, while environmental factors played the principal role for ACO and insulin sensitivity.
doi:10.2337/dc11-2060
PMCID: PMC3379613  PMID: 22596174
13.  Gene-Vitamin D Interactions on Food Sensitization: A prospective birth cohort study 
Allergy  2011;66(11):1442-1448.
Background
It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. We aim to examine if cord blood VDD is associated with FS and if such association can be modified by genetic variants in a prospective birth cohort.
Methods
This study included 649 children who were enrolled at birth and followed from birth onward at the Boston Medical Center. We defined VDD as cord blood 25(OH)D < 11ng/ml, and FS as specific IgE ≥ 0.35kUA/L to any of eight common food allergens in early childhood. We genotyped potentially functional single nucleotide polymorphisms (SNPs) in 11 genes known to be involved in regulating IgE and 25(OH)D concentrations. Logistic regressions were used to test the effects of VDD on FS individually and jointly with SNPs.
Results
Among the 649 children, 44% had VDD and 37% had FS. When examined alone, VDD was not associated with FS. When examined jointly with SNPs, a significant interaction between IL4 gene polymorphism (rs2243250) and VDD (pinteraction=0.003, pFDR=0.10) was found: VDD increased the risk of FS among children carrying CC/CT genotypes (OR=1.79, 95%CI: 1.15–2.77). Similar but weaker interactions were observed for SNPs in MS4A2 (rs512555), FCER1G (rs2070901), and CYP24A1 (rs2762934). When all four SNPs were simultaneously considered, a strong gene-VDD interaction was evident (pinteraction=9×10−6).
Conclusions
Our data demonstrate that VDD may increase the risk of FS among individuals with certain genotypes, providing evidence of gene-vitamin D interaction on FS.
doi:10.1111/j.1398-9995.2011.02681.x
PMCID: PMC3189275  PMID: 21819409
cord blood plasma 25(OH)D; food sensitization; gene-vitamin D deficiency interaction; SNP
14.  Short Sleep Duration Is Associated with Insulin Resistance Independent of Adiposity in Chinese Adult Twins 
Sleep medicine  2011;12(9):914-919.
Objective
To investigate the association between sleep duration and insulin resistance in rural Chinese adults and examine whether any such associations are independent of adiposity.
Methods
This is a cross-sectional analysis of 854 men and 640 women aged 20 to 70 years from the Anqing Twin Cohort. The following measures were obtained for each subject: Body mass index (BMI) and percentage of trunk fat (%TF), fasting plasma glucose, homeostatic model assessment of insulin resistance index (HOMA-IR), self-reported sleep duration, and measures of snoring and sleep disturbance from the Pittsburgh Sleep Quality Indices (PSQI) questionnaire modified for a Chinese population. Multivariate linear regressions were applied to examine the association of sleep duration with HOMA-IR, with and without adjustment for adiposity variables, along with other relevant covariates.
Results
In this sample of relatively lean rural Chinese adults, short sleep duration was associated with HOMA-IR in women but not in men. In women, short (≤7 hrs/night) sleep duration was associated with a higher HOMA-IR (p=0.003) compared with normal sleep duration (>7 to ≤8 hrs/night) after adjustment for all the covariates except adiposity. Further adjustment for BMI or %TF attenuated the sleep-HOMA-IR association, but the association remained significant upon adjustment for BMI (p=0.013); and upon adjustment for %TF (p=0.026). Long sleep duration (>8 hrs/night) was not significantly associated with HOMA-IR.
Conclusion
In this rural Chinese cohort, short sleep duration is independently associated with increased insulin resistance among women only, even after adjusting for adiposity and other potential confounders.
doi:10.1016/j.sleep.2011.04.006
PMCID: PMC3210935  PMID: 21940204
sleep duration; insulin resistance; adiposity; gender; rural; adults
15.  Association between Short Sleep Duration and the Risk of Sensitization to Food and Aero Allergens in Rural Chinese Adolescents 
Background
Both long and short sleep duration have been associated with obesity, cardiovascular disease, and diabetes. However, there have been no previous studies investigating the potential relationship between altered sleep duration and allergen sensitization.
Objective
To explore the association between sleep duration and sensitization to food and aeroallergens.
Methods
This study includes 1534 rural Chinese adolescent twins aged 12 to 21 years who completed standard sleep questionnaires and skin prick tests (SPTs) to 9 food and 5 aeroallergens. Total sleep time was defined as the interval from bedtime to wake-up time minus sleep latency. Sensitization was defined as having at least one positive SPT.
Results
Compared to individuals with the highest (3rd) tertile of sleep duration, those who slept less were more likely to be sensitized to any food allergen with odds ratios (ORs) of 1.9 (95% confidence interval(CI):1.3–2.7) and 1.4 (95%CI:1.0–1.9) for the 1st and 2nd tertiles (trend test Ptrend=3×10−4), respectively. The corresponding ORs for sensitization to any aeroallergen were 1.5 (95%CI: 1.1–2.0) and 1.3 (95%CI:1.0–1.7) (Ptrend=8×10−3). These associations were independent of percent body fat. In addition, we observed a significant dose-response association between the number of positive SPTs and percentage of shortest sleep duration (1st tertile) (Ptrend=1×10−3).
Conclusions and Clinical Relevance
In this sample of relatively lean rural Chinese adolescents, we found that short sleep duration was associated with increased risk of sensitization to food and aeroallergens, independent of percent body fat. Longitudinal studies are needed to further determine the temporal and causal relationships. If short sleep duration indeed is one of the risk factors for allergic sensitization, the global burden of allergic diseases could be dramatically reduced by providing appropriate guidance on sleep duration for youth.
doi:10.1111/j.1365-2222.2010.03677.x
PMCID: PMC3056931  PMID: 21255141
sleep duration; skin prick test; allergen; sensitization; adolescent
16.  Tracking Blood Glucose and Predicting Prediabetes in Chinese Children and Adolescents: A Prospective Twin Study 
PLoS ONE  2011;6(12):e28573.
We examined the tracking of blood glucose, the development of prediabetes, and estimated their genetic contributions in a prospective, healthy, rural Chinese twin cohort. This report includes 1,766 subjects (998 males, 768 females) aged 6–21 years at baseline who completed a 6-year follow-up study. Oral glucose tolerance test was performed for all subjects at both baseline and follow-up. We found that subjects with low fasting plasma glucose (FPG) or 2 h post-load glucose (PG) levels at baseline tended to remain at the low level at follow-up. Subjects in the top tertile of baseline plasma glucose tended to have a higher risk of developing prediabetes at follow-up compared to the low tertile: in males, 37.6% vs. 27.6% for FPG and 37.2% vs. 25.7% for 2hPG, respectively; in females, 31.0% vs. 15.4% for FPG and 28.9% vs. 15.1% for 2 h PG, respectively. Genetic factors explained 43% and 41% of the variance of FPG, and 72% and 47% for impaired fasting glucose for males and females, respectively; environmental factors substantially contribute to 2hPG status and impaired glucose tolerance. In conclusion, in this cohort of healthy rural Chinese children and adolescents, we demonstrated that both FPG and 2hPG tracked well and was a strong predictor of prediabetes. The high proportion of children with top tertile of blood glucose progressed to prediabetes, and the incidence of prediabetes has a male predominance. Genetic factors play more important role in fasting than postload status, most of which was explained by unique environmental factors.
doi:10.1371/journal.pone.0028573
PMCID: PMC3233591  PMID: 22163315
17.  Prediabetes Is not All About Obesity: Association between Plasma Leptin and Prediabetes in Lean Rural Chinese Adults 
Objective
This study investigated the associations of plasma leptin levels with insulin resistance (IR) and prediabetes in relatively lean, rural Chinese men and women.
Design and methods
This study included 574 subjects aged 21–45 years from a community-based twin cohort. Plasma leptin concentrations were measured by sandwich immunoassays using flowemetric xMAP technology. Prediabetes was defined based on fasting plasma glucose and 75g oral glucose tolerance test. Multivariate linear and logistic regression analyses were used to investigate gender-specific associations of leptin with IR measures and prediabetes, adjusting for intra-twin correlation, measures of adiposity, and other pertinent covariates.
Results
The body mass index(BMI) is 22.3±2.7 kg/m2 in men and 22.5±2.7 kg/m2 in women. Leptin levels were positively associated with IR. Individuals with higher tertiles of leptin also had increased risk of prediabetes with OR of 2.6 (95%CI: 1.4–5.1) and 4.3 (95%CI: 2.1–8.7) in men; OR of 1.1 (95%CI: 0.6–2.1) and 3.1 (95%CI 1.5–6.2) in women for 2nd and 3rd tertile, respectively. These associations were attenuated after further adjusting for adiposity measurements only in men. The Leptin-prediabetes associations disappeared after adjusting for the homeostatic model assessment of insulin resistance (HOMA-IR) in both genders.
Conclusion
In this sample of relatively lean rural Chinese adults, plasma leptin levels were associated with IR and prediabetes in a dose-response fashion, which were not totally explained by adiposity. Our data underscored that prediabetes is not all about obesity, and leptin may be an additional biomarker for screening individuals at high risk for prediabetes in this population.
doi:10.1530/EJE-10-0145
PMCID: PMC3163476  PMID: 20511357
Leptin; insulin resistance; prediabetes; Chinese
18.  Percent Fat Mass Is Inversely Associated With Bone Mass and Hip Geometry in Rural Chinese Adolescents 
Journal of Bone and Mineral Research  2010;25(7):1544-1554.
This study was an attempt to examine the phenotypic, genetic, and environmental correlations between percent fat mass (PFM) and bone parameters, especially hip geometry, among 786 males and 618 females aged 13 to 21 years from a Chinese twin cohort. PFM, bone area (BA), bone mineral content (BMC), cross-sectional area (CSA), and section modulus (SM) were obtained by dual-energy X-ray absorptiometry. Multiple linear regression models were used to assess the PFM-bone relationships. A structural equation model for twin design was used to estimate genetic/environmental influences on individual phenotype and phenotypic correlations. After controlling for body weight and other pertinent covariates, we observed inverse associations between PFM and bone parameters: Compared with the lowest age- and gender-specific tertile of PFM, males in the highest tertile of PFM had lower measures of whole-body-less-head BA (WB-BA), lumbar spine BA (L2–L4-BA), total-hip BA (TH-BA), total-hip BMC, CSA, and SM (p < .005 for all, adjusted p < .05). Similar inverse associations were observed in females for all the preceding parameters except WB-BA and L2–L4-BA. These associations did not vary significantly by Tanner stages. In both genders, the estimated heritabilities were 80% to 86% for BMC, 67% to 80% for BA, 74% to 77% for CSA, and 64% for SM. Both shared genetics and environmental factors contributed to the inverse PFM-bone correlations. We conclude that in this sample of relatively lean Chinese adolescents, at a given body weight, PFM is inversely associated with BA, BMC, and hip geometry in both genders, and such associations are attributed to both shared genetic and environmental factors. © 2010 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.40
PMCID: PMC3153997  PMID: 20200956
percent fat mass; hip geometry; bone mineral content; adolescence; coheritability
19.  Genetic and Environmental Contributions to Allergen Sensitization in a Chinese Twin Study 
Background:
Allergic disease is on the rise worldwide. Effective prevention of allergic disease requires comprehensive understanding of the factors that contribute to its intermediate phenotypes, such as sensitization to common allergens.
Objective:
To estimate the degree of genetic and environmental contributions to sensitization to food or aeroallergens.
Methods:
Sensitization was defined as a positive skin prick test to an allergen. We calculated the zygosity-specific concordance rates and odds ratios (ORs) for sensitization to food and aeroallergens in 826 Chinese twin pairs (472 MZ and 354 DZ) aged 12 to 28 years. We also applied structural equation modeling procedures to estimate genetic and environmental influences on sensitization.
Results:
The concordance rates and risk of sensitization in one twin given the presence vs. the absence of sensitization in the other twin were higher in MZ twins than those in DZ twins. However, a large number of MZ twins were discordant in sensitization to common allergens. These observations suggest both genetic and environmental factors influence sensitization. Consistently, the estimated heritability and individual environmental components of the liability to sensitization ranged from 0.51 to 0.68 and 0.32 to 0.49, respectively, based on the best-fitted structural equation model. We also observed high phenotypic correlations between sensitization to two aeroallergens (cockroach and dust mite: 0.83) and two food allergens (peanut and shellfish: 0.58), but only moderate correlations for the pairs between sensitization to a food and an aeroallergen (0.31-0.46). The shared genetic and environmental factors between paired sensitizations contribute to the observed correlations.
Conclusion:
We demonstrated that sensitization to common food and aeroallergens were influenced by both genetic and environmental factors. Moreover, we found that paired allergen sensitizations might share some common sets of genes and environmental factors. This study underscores the need to further delineate unique and/or pleiotropic genetic and environmental factors for allergen sensitization.
doi:10.1111/j.1365-2222.2009.03228.x
PMCID: PMC2756049  PMID: 19302247
Twin; sensitization; positive SPT; structural equation modeling; heritability; environmental factors
20.  Association of genetic ancestry with preterm delivery and related traits among African American mothers 
OBJECTIVE
In the United States, the rate of preterm delivery (PTD) is higher in African Americans (17.8%) than non-Hispanic whites (11.5%). Such disparity cannot be fully explained by differences in socioenvironmental factors.
STUDY DESIGN
We genotyped 812 mothers in a case-control PTD study at Boston Medical Center who self-reported their ethnicity as “black.” Regression analysis and Wilcoxon rank-sum test were applied to evaluate ancestral distribution and the association between genetic ancestry and PTD-related traits, as well as the potential confounding effect of population stratification.
RESULTS
The estimated African ancestral proportion was 0.90 ± 0.13. We found significant associations of ancestral proportion with PTD as a whole and PTD subgrouped by the presence of maternal hypertensive disorders. We did not observe significant confounding as a result of population stratification in this case-control PTD study.
CONCLUSION
Our data underline the need for more intensive investigation of genetic admixture in African Americans to identify novel susceptibility genes of PTD.
doi:10.1016/j.ajog.2009.02.027
PMCID: PMC2859981  PMID: 19446788
admixture; genetic ancestry; population stratification
21.  Maternal cigarette smoking, metabolic gene polymorphisms, and preterm delivery: new insights on G×E interactions and pathogenic pathways 
Human genetics  2008;123(4):359-369.
Preterm delivery (PTD, <37 weeks of gestation) is a significant clinical and public health problem. Previously, we reported that maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 synergistically increase the risk of low birth weight. This study investigates the relationship between maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 with preterm delivery (PTD) as a whole and pre-term subgroups. This case–control study included 1,749 multi-ethnic mothers (571 with PTD and 1,178 controls) enrolled at Boston Medical Center. After adjusting covariates, regression analyses were performed to identify individual and joint associations of maternal smoking, two functional variants of CYP1A1 and GSTT1 with PTD. We observed a moderate effect of maternal smoking on PTD (OR = 1.6; 95% CI: 1.1–2.2). We found that compared to non-smoking mothers with low-risk genotypes, there was a significant joint association of maternal smoking, CYP1A1 (Aa/aa) and GSTT1 (absent) genotypes with gestational age (β = −3.37; SE = 0.86; P = 9 × 10−5) and with PTD (OR = 5.8; 95% CI: 2.0–21.1), respectively. Such joint association was particularly strong in certain preterm subgroups, including spontaneous PTD (OR = 8.3; 95% CI: 2.7–30.6), PTD < 32 weeks (OR = 11.1; 95% CI: 2.9–47.7), and PTD accompanied by histologic chorioamnionitis (OR = 15.6; 95% CI: 4.1–76.7). Similar patterns were observed across ethnic groups. Taken together, maternal smoking significantly increased the risk of PTD among women with high-risk CYP1A1 and GSTT1 genotypes. Such joint associations were strongest among PTD accompanied by histologic chorioamnionitis.
doi:10.1007/s00439-008-0485-9
PMCID: PMC2852624  PMID: 18320229
22.  Adiposity, serum lipid levels, and allergic sensitization in Chinese men and women 
Background
Obesity and allergic diseases have increased dramatically in recent decades. While adiposity has been associated with asthma, associations with allergic sensitization have been inconsistent.
Objective
To examine the association of adiposity and lipid profiles with allergic sensitization.
Methods
This study included 1,187 rural Chinese twins (653 men) aged 18-39 years, with skin prick tests (SPT), anthropometric and DEXA-assessed adiposity measures, and lipid assessments. Allergic sensitization was defined as positive SPT to ≥1 allergen (9 foods and 5 aeroallergens tested). We applied gender-stratified generalized estimating equations to assess the association of adiposity and serum lipids with allergic sensitization, and structural equation models to estimate the genetic/environmental influences on any observed associations.
Results
Males had lower percent body fat (%BF) (13.9% vs. 28.8%) but higher rates of allergic sensitization (56.2% vs. 36.7%) than females. Males in the highest %BF quartile were 2.1 times more likely sensitized than the lowest quartile (95%CI 1.3-3.5, P-trend=0.003). In males, the risk of allergic sensitization increased with HDL<40 mg/dl (OR=4.0, 95%CI 1.8-9.2) and higher LDL quartiles (P-trend=0.007). This appeared to be partially explained by shared genetic factors between serum lipid levels and allergic sensitization. In females, lower HDL was associated with increased risk of allergic sensitization.
Conclusions
In this relatively lean Chinese population, higher %BF, lower HDL and higher LDL were associated with greater risk of allergic sensitization, most notable in males. The observed associations between adiposity, serum lipids and allergic sensitization in males appear to be partially explained by common genetic influences on these traits.
doi:10.1016/j.jaci.2008.11.032
PMCID: PMC2697621  PMID: 19135238
DEXA; Body mass index; Adiposity; Serum lipids; Sensitization
23.  Dissociation between the Prevalence of Atopy and Allergic Disease in Rural China among Children and Adults 
Background
The prevalence of allergic diseases is increasing worldwide, but the reasons are not well understood. Previous studies suggest that this trend may be associated with lifestyle and urbanization.
Objective
To describe patterns of sensitization and allergic disease in an unselected agricultural Chinese population.
Methods
The data was derived from a community-based twin study in Anqing, China. Skin prick testing was performed to foods and aeroallergens. Atopy was defined as sensitization to ≥1 allergen. Allergic disease was ascertained by self-report. The analysis was stratified by sex and age (children [11-17 years] and adults [≥18 years]) and included 1059 same-sex twin pairs.
Results
Of 2118 subjects, 57.6% were male (n=1220). Ages ranged from 11-71 years; 43.3% were children (n=918). Atopy was observed in 47.2% (n=999) of participants. The most common sensitizing foods were shellfish (16.7%) and peanut (12.3%). The most common sensitizing aeroallergens were dust mite (30.6%) and cockroach (25.2%). Birth order and zygosity had no effect on sensitization rates. Multivariate logistic regression models revealed risk factors for sensitization include age for foods and sex for aeroallergens. The rates of food allergy and asthma were estimated to be <1%.
Conclusions
Atopic sensitization was common in this rural farming Chinese population, particularly to shellfish, peanut, dust mite, and cockroach. The prevalence of allergic disease, in contrast, was quite low.
Clinical Implications
Allergen sensitization was far more common than the rate of self-reported allergic disease in this community. Evidence of sensitization is an inadequate marker of allergic disease and better correlates with clinical disease are needed.
Capsule summary
Among this large unselected Chinese rural farming community, atopy was observed in nearly half of the study subjects, but the rate of allergic disease was comparatively very low.
doi:10.1016/j.jaci.2008.08.009
PMCID: PMC2747487  PMID: 18805578
aeroallergens; rural; farming community; Chinese; food allergens; prevalence; sensitization; skin prick tests

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